The invention relates to a novel process for treating stress in a subject suffering from at least one symptom of stress. More specifically, the invention relates to the use of precursors or prodrugs that enhance serotonin-mediated neurotransmission, as well as intermediates in the biosynthesis of serotonin, for treating stress in such a subject.
Individuals responding to stressful events can experience one, two or three of the following stages: (1) stage one, mobilization of energy; (2) stage two, exhaustion or consuming energy; and (3) stage three, draining energy stores.
In stage one, the mobilization of energy, the body responds to stress through a release of Adrenalin and a fight or flight response. Symptoms of this stage include increased heart rate and blood pressure, rapid breathing, sweating, decreased digestion rate and indigestion.
If there is no relief from stage one, the individual enters phase two, exhaustion or consuming energy. Here, the body will begin to release stored sugars and use up fats. Symptoms of this stage include feeling driven, feeling pressured, tiredness and fatigue, increased smoking, coffee drinking and/or alcohol consumption, anxiety, memory loss, and acute illnesses such as colds and flu.
If either the stressful situation is not resolved, or the individual""s reaction to the situation is not changed, the individual enters phase three, draining energy sources. Here, the individual becomes chronically stressed, and the body""s need for energy resources outpaces its ability to produce them. Symptoms of this stage include serious illnesses such as heart disease, ulcers, and mental illness, as well as insomnia, errors in judgment, and personality changes.
At present, patients suffering from stress related disorders are treated for the symptoms of stress by the use of pharmaceutical compositions containing drugs such as anxiolytics or sometimes with beta-blockers. Anxiolytics frequently used include drugs such as benzodiazepines, diazepam being a specific example. The beta-blocking drugs used for treatment of such patients include propranolol. The use of these classes of drugs for such treatments is discussed in Goodman and Gilman""s Pharmacological Basis of Therapeutics, Seventh Edition, 1985, Alfred G. Gilman et al., editors, pages 192-201, the entirety of which is herein incorporated by reference.
The serotoninergic drug fenfluramine is known to be an effective drug for treating obesity. The racemic mixture, D,L-fenfluramine, is disclosed in U.S. Pat. No. 4,452,815 as being effective for inhibiting the abnormal craving for carbohydrates which afflicts some people and is associated with obesity. Dexfenfluramine is also indicated for use in treating patients who cannot control their eating habits or appetite. The use of dexfenfluramine for this purpose was disclosed in U.S. Pat. No. 4,309,445. In both of these patents, fenfluramines were used for treating a patient""s appetite or craving for certain types of food. Nowhere in these patents is the use of fenfluramines taught or suggested for treatment of stress or stress symptoms.
Wurtman, et al., in Brain Serotonin, Carbohydrate-Craving, Obesity and Depression, Obesity Research, vol. 3, suppl. 4, Nov. 4, 1995, pages 477S-480S present a theoretical mechanism by which fenfluramines work for suppressing appetite for certain food types, the entirety of which is herein incorporated by reference. Dexfenfluramine is shown in this publication to be useful for treating obesity suffered by such people, but there is no teaching or suggestion that dexfenfluramine is useful for treating stress itself.
Wurtman et al. describes the serotoninergic fenfluramines as acting to facilitate weight loss in subjects in three ways:
xe2x80x9cThey accelerate the onset of satiety and enhance basal metabolic rate by about 100 calories per day. They also inhibit the xe2x80x98carbohydrate cravingxe2x80x99 manifested by many people who are overweight or are becoming so, and there is reason to believe that this inappropriate eating behavior actually constitutes a xe2x80x98serotonin hungerxe2x80x99 by the brain, in which case giving the serotoninergic drug might constitute a specific therapy for the etiologic process causing the obesity.xe2x80x9d
Further discussion of the known functioning of fenfluramines is found in Wurtman, et al., Brain Serotonin, Carbohydrate-Craving, Obesity and Depression, Recent Advances in Tryptophan Research, G. A. Filippini, et al. eds., Plenum Press, New York, 1996, pages 35-41 the entirety of which is herein incorporated by reference.
The use of dexfenfluramine for treating animals inflicted with periodic pain is discussed in Dexfenfluramine: Effects on Food Intake in Various Animal Models, Rowland, et al., Clinical Neuropharmacology, vol. 11, suppl. 1, pp. S33-S50 the entirety of which is herein incorporated by reference. This article indicates in the abstract that: xe2x80x9c. . . both stress-induced eating as well as a food-motivated response (running) are particularly sensitive to inhibition by dexfenfluramine.xe2x80x9d
Rowland et al. discloses the administration of dexfenfluramine to rats exhibiting increased eating behavior in response to tail pinching. Dexfenfluramine (DF) was found to decrease the eating behavior of the tail pinched rats.
Rowland, et al., discusses the implications of their experiments with regard to stress-induced eating as follows on page S37, wherein DF refers to dexfenfluramine:
xe2x80x9cMild tail pressure induces eating and gnawing in rats, and this may be a model of stress-induced eating in humans. Garattini reported that DF potently inhibits tail pressure-induced eating, and that the DI50 of 0.6 mg/kg is about one-half of the doses effective in the other paradigms reviewed so far. It was previously reported that racemic fenfluramine inhibits tail pressure-induced eating as well as concurrent behaviors such as gnawing, locomotion, and vocalization. In the study with DF, only the amount eaten was reported, rather than all oral behaviors. These data thus suggest that DF may be an especially potent inhibitor of stress-related eating. Further studies are needed to clarify the effect of DF on other oral behaviors, as well as whether it has xe2x80x98antistressxe2x80x99 effects along with its anorectic action.xe2x80x9d
Rowland, et al., indicate only that fenfluramines inhibit tail pinching-induced eating and other behaviors stemming from the tail pinching protocol in rats. Rowland, et al. did not teach or suggest that fenfluramines can be used as a treatment for reducing stress itself. Thus, until the present invention, it was only known that dexfenfluramine inhibits eating in rats which have had their tails pinched. It was not previously known whether dexfenfluramine or d,1-fenfluramine in particular, or serotoninergic drugs in general, would be effective for treatment of stress. One skilled in the art would not have been led by the results of Rowland, et al. in rats, to treat humans suffering from stress with dexfenfluramine.
A need continues to exist for improved and alternative methods and compositions for treating stress and symptoms related thereto.
Briefly, the present invention is a novel treatment for stress and symptoms of stress in a subject. The applicants have discovered that administering precursors or prodrugs that enhance serotonin-mediated neurotransmission to a patient in need thereof can bring about a reduction in the stress felt by the patient and the symptoms of stress manifested by the patient. The treatment of stress and stress related symptoms of a patient with the compounds of the present invention has not been previously reported.
The present invention provides an appropriate treatment for stress in human patients, especially those suffering from stress-induced overeating. This invention is based on the discovery that prodrugs of serotonin, or intermediates in the biosynthesis of serotonin, such as tryptophan or 5-hydroxytryptophan, or their salts, can alleviate symptoms of stress in patients, when administered in effective amounts or at appropriate dosages.
Accordingly, the present invention is directed to a method of treating a human subject exhibiting one or more symptoms of stress, which comprises administering to the subject an effective amount of a compound which enhances serotonin-mediated neurotransmission such as d,1-fenfluramine or dexfenfluramine, or a pharmaceutically acceptable salt thereof. In a specific embodiment of the invention, when the fenfluramine is d,1-fenfluramine or a pharmaceutically acceptable salt thereof, an effective dose ranges from about 15 to about 150 mg/day, preferably from about 40 to about 80 mg/day. When the fenfluramine is dexfenfluramine or a pharmaceutically acceptable salt thereof, an effective dose ranges from about 5 to about 150 mg/day, preferably from about 15 to about 45 mg/day.
The present invention is further directed to a method of treating a human subject exhibiting one or more symptoms of stress, which comprises administering to the subject an effective amount of a precursor or prodrug that enhances serotonin-mediated neurotransmission, such as tryptophan or 5-hydroxytryptophan, or a pharmaceutically acceptable salt thereof. In a specific embodiment of the invention, when either tryptophan or 5-hydroxytryptophan or a pharmaceutically acceptable salt thereof is administered, an effective dose ranges from about 20 mg to about 4 g/day, preferably from about 50 mg to about 1 g/day, more preferably about 50 mg to about 400 mg/day, and most preferably about 100 mg/day.
According to the present invention, a treatment is provided which results in a reduction in the stress level of the patient experiencing emotional and other kinds of stress.
Accordingly, it is an object of the invention to provide a treatment for stress and symptoms related thereto.
It is another object of the invention to provide a treatment for stress which is also useful for controlling food intake in a either a stress-induced overeating patient or a stress-induced undereating patient.
It is another object of the invention to provide a treatment for non-eating related stress symptoms of a patient including but not limited to increased blood sugar in the diabetic patient, fatigue, insomnia, depression, high blood pressure, headaches, digestive changes, neck pain, back ache, tension, anxiety, anger, obsessive thinking reclusiveness, pessimism, increased irritability, inability to concentrate, inability to perform at ones previous level, and the like.
It is another object of the invention to provide a treatment for stress in a patient, wherein the treatment is with a drug other than an anxiolytic or beta-blocking drug.
Other objects will become apparent from the description of the invention which follows.
Stress is classified by convention as being either acute or chronic in nature. A patient suffering from a stress related disorder can exhibit a variety of types of symptoms. These symptoms can include increased blood sugar in the diabetic patient, fatigue, insomnia, depression, high blood pressure, headaches, digestive changes, neck pain, back ache, tension, anxiety, anger, sadness, impairment of self esteem, reclusiveness, pessimism, increased irritability, inability to concentrate, inability to perform at ones previous level, obsessive thinking overeating, under eating, and the like. Disclosed herein is a novel treatment method for stress in a patient, which method uses drugs hitherto unknown as useful for treating stress. The novel method disclosed herein provides a useful method for treating patients suffering from stress and exhibiting at least one symptom thereof. In a specific embodiment of the invention, said method has been found particularly useful for treating stress felt by subjects who also suffer from overeating disorders or who overeat in reaction to the stress that they are experiencing.
The method and agents of the invention are also used to treat normal patients, that is, patients with no overt symptoms of stress. Thus the methods of the invention are used prophylactically to prevent, delay, diminish, or attenuate the onset of stress and stress-related symptoms. The methods disclosed herein are used for people who have been, or will soon be, exposed to a stressful environment or situation, but before onset of increased heart rate, rapid breathing, sweating, decreased digestion, or indigestion.
The applicants"" experiments have now permitted the discovery that such antistress effects can be achieved with serotoninergic drugs in general and 5-hydroxytryptophan in particular.
According to the present invention, a novel method for treating stress comprises the administration of stimulators of serotonin-mediated neurotransmission, to a patient with stress related symptoms. In a preferred embodiment, the method comprises the administration of effective amounts of either tryptophan or 5-hydroxytryptophan, or their salts.
Drugs that reduce the effects of stress in a patient might not necessarily be useful in all obese patients. Some people who overeat respond to stress by reducing their eating, not increasing their eating behavior. According to the present invention, the stress reducing drugs that prove to be the most useful for weight reduction are those that elicit in patients, whose overeating is stress associated, a response that leads to a reduction in their eating behavior. Similarly, the stress reducing drugs that prove to be the most useful for weight gain are those that elicit in patients, whose under eating is stress associated, a response that leads to a gain in their eating behavior
A number of compounds stimulate or enhance serotonin-mediated neurotransmission, sometimes referred to as serotoninergic drugs, and are thus useful in treating humans with one or more symptoms of stress. These compounds include the following: D,L-fenfluramine, dexfenfluramine, tryptophan, lithium, chlorimipramine, cyanimipramine, fluoxetine, paroxetine, fluvoxamine, citalopram, femoxitine, cianopramine, sertraline, sibutramine, venlafaxine, ORG 6582, RU 25591, LM 5008, DU 24565, indalpine, CGP 6085/A, WY 25093, alaprociate, zimelidine, trazodone, amitriptyline, imipramine, trimipramine, doxepin, protriptyline, nortriptyline, dibenzoxazepine, deprenyl, isocarboxazide, phenelzine, tranylcypromine, furazolidone, procarbazine, moclobemide, brofaromin, nefazodone, bupropion, MK 212, DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, xcex1-methyl-5-HT, TFMPP, bufotenin, Ru 24969, quipazine, 5-carboxyamidotryptamine, sumatriptan, CGS 12066, 8-OH-DPAT, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H404, (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1,2-b)pyrrol-1-yl)-1-methylethylamine 1:1 C4H404, SB 206553, and pharmaceutically acceptable salts thereof. Suitable salts can be formed from the above compounds, for example, as addition salts using the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid or organic acids such as acetic acid, maleic acid, valeric acid, caproic acid, benzoic acid and nicotinic acid.
xe2x80x9cFenfluraminesxe2x80x9d is used in the present application as meaning a racemic mixture of D,L-fenfluramine, which is also called N-ethyl-xcex1-methyl-3-(trifluoro-methyl)benzeneethanamine; the dextrorotatory isomer known as dexfenfluramine and also as D-fenfluramine; or the pharmaceutically acceptable salts of these compounds. Suitable salts can be formed from dexfenfluramine or D,L-fenfluramine, for example, as addition salts using the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid or organic acids such as acetic acid, maleic acid, valeric acid, caproic acid, benzoic acid and nicotinic acid.
The serotoninergic drugs MK-212, DOI, m-CPP, Ro 60-0175/ORG 35030, Ro 60-0332/ORG 35035, Ro 60-0175, Org 12962, Ro 60-0332, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H404, (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno(1, 2-b)pyrrol-1-yl)-1-methylethylamine 1:1 C4H404, and SB 206553 fall into the class of drugs which activate postsynaptic receptors. These are agonist drugs which bombard the serotonin receptors of postsynaptic cells and mimic the effect of large amounts of serotonin reacting with the postsynaptic cells"" serotonin receptors. Examples of the use of three of these drugs along with the chemical names and sources thereof are shown in EXAMPLES 13-15.
6-Chloro-2-(1-piperazinyl)pyrazine (MK-212), can be obtained from Merck and Co., Inc. Whitehouse Station, N.J. (S)-2-(4, 4, 7-trimethyl-1, 4-dihydro-indeno (1, 2-B) pyrrol-1-yl-)-1-methyl-ethylamine (Ro 60-175/ORG 35030) can be obtained from F. Hoffmann-LaRoche Ltd., Basel, Switzerland. (S)-2-(Chloro-5-fluoro-indol-1-yl)-1-methylethylamine (Ro 60-0332/ORG 35035) is obtained from F. Hoffmann LaRoche Ltd., Basel, Switzerland. 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) can be obtained from Research Biochemical International, Natick, Mass. 1-(3-Chlorophenyl)piperazine (m-CPP) can be obtained from Research Biochemical International, Natick, Mass.
Other drugs, preferably halogenated amphetamines, can also be useful to treat stress in a subject. Such other useful drugs can include specific drugs that are not halogenated amphetamines including, but not limited to, effexor, nefazodone, bupropion, paroxetine, fluoxetine, and sertralin.
Because serotonin present in the bloodstream is excluded by the blood-brain barrier from entry into the brain, the administration of precursors such as L-tryptophan (L-TP) or L-5-hydroxytryptophan (L-5-HTP) is used to increase brain concentrations of serotonin (Wurtman and Fernstrom (1975) xe2x80x9cControl of brain monoamine synthesis by diet and plasma amino acids.xe2x80x9d The American Journal of Clinical Nutrition, 28, 638-647), incorporated herein by reference in its entirety. The daily supplementation of precursors for serotonin comprises administering, for an effective daily period, an effective amount of L-tryptophan or preferably L-5-hydroxytryptophan as the intermediate precursors for serotonin (5-hydroxytryptamine). It is understood that any of its L, D or racemic forms are suitable, but preferably precursors are in L form. Furthermore, one skilled in the art will know to make tryptophan from 3-indolacetic acid or 3-indolpyruvic acid or use these acids as alternative to tryptophan and thus avoid the hepatic degradation by tryptophan pyrrolase. Other precursors or intermediates thereof are equally suitable with or without further modification, including but not limited to diethyl N-benzyloxycarbonyl-5-benzyloxycarbonyloxy-L-tryptophyl-L-aspartate, dibenzyl N-benzyloxycarbonyl-5-hydroxy-L-tryptophanylaspartate, 5-Hydroxy-L-tryptophyl-L-aspartic acid trihydrate, diethyl N-benzyloxycarbonyl-5-hydroxy-L-tryptophyl-L-glutamate, diethyl 5-hydroxy-L-tryptophyl-L-glutamate hydrochloride, dibenzyl L-benzyloxycarbonyl-5-hydroxytryptophyl-L-glutamate, 5-hydroxy-L-tryptophyl-L-glutamic acid, pentachlorophenyl ester of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan, methyl ester of N-benzyloxycarbonyl-5-hydroxy-L-tryptophyl-L-tyrosine, N-Acetyl-5-hydroxy-L-tryptophan, methyl ester of N-acetyl-5-hydroxy-L-tryptophyl-L-tyrosine, methyl ester of n-acetyl-5-hydroxy-L-tryptophyl-5-hydroxy-L-tryptophan, 5-hydroxy-L-tryptophyl-L-alanine hydrate, 5-hydroxy-L-tryptophan-L-valine, 5-hydroxy-L-tryptophyl-L-leucine, 5-hydroxy-L-tryptophyl-L-proline, 5-hydroxy-L-tryptophyl-L-phenylalanine, 5-hydroxy-L-tryptophyl-5-hydroxy-L-tryptophan, 5-hydroxy-L-tryptophyl-L-tryptophan, 1-5-hydroxytryptophyl-L-serine, 5-hydroxy-L-tryptophyl-L-arginine, 5-hydroxy-L-tryptophylglycine, 5-hydroxy 1-tryptophyl-gamma-aminobutyric acid, 5-hydroxy-L-tryptophanamide hydrate, methyl ester of 5-hydroxy-L-tryptophyl-L-histidine, benzyl ester of L-5-hydroxytryptophan, benzyl ester of N-benzyloxycarbonyl-5-hydroxy-L-tryptophyl-5-hydroxy-L-tryptophan, 5-Hydroxy-L-tryptophyl-5-hydroxy-L-tryptophan hemihydrate, 5-hydroxytryptophan inosinate, theophylline salt of (DL) 5-hydroxytryptophan, and the like.
These serotonin precursors can be administered alone or in combination with the stimulants of serotonin synthesis including but not limited to vitamin B1, vitamin B3, vitamin B6, biotin, S-adenosylmethionine, folic acid, ascorbic acid, magnesium, coenzyme Q10, and piracetam.
Alternatively and additionally one skilled in the art will know to include serotoninergic drugs that act as serotonin agonists including but not limited to ergolide mesylate, pergolide mesylate, buspirone, (3 beta)-2,3-dihydrolysergine, (3 beta)-2,3-dihydroisolysergine, (3 beta)-2,3-dihydrolysergol, (3 beta)-2,3-dihydrolysergene, (3 beta, 5 beta, 8 beta)-9,10-didehydro-2,3-dihydro-6-methyl-8-(methylthiomethyl) ergoline, (3 beta, 5 beta, 8 beta)-9,10-didehydro-2,3-dihydro-6-methylergoline-8-ac etonitrile, (3 beta, 5 beta, 8 beta)-9,10-didehydro-2,3-dihydro-6-methyl-8-(phenylthiomethyl) ergoline, (3 beta, 5 beta, 8 beta)-9,10-didehydro-2,3-dihydro-6-methyl-8-(2-pyridyl thiomethyl) ergoline, (3 beta)-2,3-dihydro-methyllysergate, (3 beta, 5 beta, 8 beta)-9,10-didehydro-2,3-dihydro-8-methyl-6-propylergoline.
For practicing the invention, the active serotonin-mediated neurotransmission stimulating compound can be administered to a patient as a pharmaceutical composition comprising the active compound admixed with a pharmaceutically acceptable carrier, including one or more excipients. For example, the compound or precursor can be administered to a patient as a pharmaceutical composition comprising in a preferred embodiment either L-tryptophan or L-5-hydroxytryptophan admixed with a pharmaceutically acceptable carrier, including one or more excipients.
It is to be understood that according to the teachings of the invention, the invention can be practiced by administering serotonin-mediated neurotransmission stimulating compounds, for example, tryptophan or 5-hydroxytryptophan, to a subject as a single unit dose one or more times per day, or as a plurality of unit doses once or more times per day without deviating from the teachings of the invention.
It is to be further understood that the present invention as disclosed herein, also includes a method of making a medicament for treating stress, wherein the method comprises a step of mixing a serotonin precursor such as tryptophan or 5-hydroxytryptophan with a pharmaceutically acceptable inert ingredient.
For the purposes of this disclosure, the terms xe2x80x9csubjectxe2x80x9d and xe2x80x9cpatientxe2x80x9d are used interchangeably to refer to a human exhibiting at least one symptom of stress.
The pharmaceutically acceptable carrier, excipient, and/or inert ingredient of choice utilized for a formulation used in accordance with the invention depends on the mode of administration to a subject. The compositions of this invention are suitable for oral, parenteral, buccal, sublingual or rectal administration. The resulting pharmaceutical compositions are, for example, tablets, coated tablets, capsules, soft gelatin capsules, drinkable emulsions, suspensions or solutions for oral or injectable administration, sublingual tablets or suppositories. They can also be formulated into a sustained release form. Among the various excipients which can be used for these purposes include talc, magnesium phosphate, lactose or silica or the like. To the solid forms can be added a filler, a diluent, a binder such as ethyl-cellulose, dihydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, gum arabic, gum tragacanth or gelatin. The compositions of this invention can also be flavored, colored or coated with a wax or a plasticizer.
The compositions of this invention can also be administered through sachets to which the subject adds water, or as a food based preparation, functional food, dietary supplement or nutraceutical. For the purposes of this application, xe2x80x9cfunctional foodxe2x80x9d is defined as a food engineered or supplemented to give improved nutritional value, xe2x80x9cdietary supplementxe2x80x9d is defined as a substance produced by isolation, or microbial culture purification that gives health benefits, and xe2x80x9cnutraceuticalxe2x80x9d is defined as a food, or parts of a food, that provide medical or health benefits, including prevention and treatment of clinical conditions and/or symptoms related thereto. The compositions of this invention can also be isolated from varying plants or components thereof including but not limited to root, tuber, rind/peel, bark, seed, fruit, bulb, flower, rhizome, leaf, stem, oil, shell, capsule, twig, resin, extract, and bean. In addition, the aforementioned components can be consumed by the subject, thereby providing the subject with the active ingredient(s) of the invention disclosed herein.
It is to be understood that those skilled in the art of pharmaceutical formulation will be able to make a variety of formulations that would be within the scope of this disclosure and the appended claims, without departing from the spirit and teachings of the invention. It is intended that all such formulations be included in this invention.
The invention will now be described through illustrative examples. The examples are not intended to limit the scope of the invention, which is limited only by the appended claims.